Atherosclerosis is an inflammatory disease resulting in the hardening and thickening of the wall of arteries and the formation of plaques, which comprise immune cells, mesenchymal cells, lipids, and extracellular matrix. The source of mesenchymal cells in the atherosclerotic plaques has been under scrutiny for years. Current endothelial-lineage tracing studies indicate that the endothelium is a source for plaque-associated mesenchymal cells. Endothelial cells can acquire a mesenchymal phenotype through endothelial-mesenchymal transition (EndMT), wherein the expression of endothelial markers and functions is lost and the expression of mesenchymal cell marker and functions acquired. Furthermore, EndMT can result in delamination and migration of endothelial cell-derived mesenchymal cells into the underlying tissue. Here, we review the contribution of EndMT in vascular disease focusing on atherosclerosis and describe the major biochemical and biomechanical signalling pathways in EndMT during atherosclerosis progression. Furthermore, we address how the well-established systemic atherosclerosis risk factors might facilitate EndMT during atherosclerosis.